This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Peripheral arterial disease (PAD) is characterized by lower limb arterial obstruction due to atherosclerosis. Most of the over 10 million in the U.S. with PAD are elderly and the prevalence is increasing. Patients with PAD are undertreated with potentially life-saving risk factor modification when compared to those with coronary disease. Presently used diagnostic methods are limited and modalities that will allow study of progression and regression of disease are clearly needed. A multi-disciplinary team from cardiology, radiology, vascular surgery, biomedical engineering, exercise science, biostatistics and clinical trials management has been assembled to develop and refine such methods. Aim #1 is to develop and test magnetic resonance imaging (MRI) methods to image the arterial wall and characterize atherosclerotic plaque in PAD. High-resolution multislice black-blood spiral MRI will be developed in normal subjects and tested in patients to rapidly survey the vessel wall and atherosclerotic plaque in the superficial femoral artery. Multi-spectral MRI will characterize plaque components in specific regions. Aim #2 is to develop and test MRI and MR spectroscopic methods in the quantification of perfusion and energetics of skeletal muscle supplied by atherosclerotic peripheral arteries. Standardized plantarflexion exercise to a specific power output in the MRI will be performed. First-pass contrast-enhanced MRI at peak exercise will quantify the severity of calf muscle hypoperfusion. Phosphorus spectra acquired during exercise recovery will identify the metabolic evidence for ischemia. MR angiography will assess luminal obstruction. Functional studies will include 6-minute walk test and treadmill exercise with measures of V02 peak. With the hypothesis that statin therapy will reduce plaque burden, stabilize plaque components, and improve measures of end-organ function. Aim #3 is to use multi-modality magnetic resonance to test the efficacy of statin therapy on the vessel wall, atherosclerotic plaque, and skeletal muscle perfusion and energetics in PAD. 90 patients with PAD with an ankle-brachial index between 0.4 and 0.9 will be studied with comprehensive MR at baseline and yearly during 4 years of therapy with a high-dose statin. These studies will enhance the understanding of statin-mediated plaque regression and stabilization and improved end organ function in PAD and lay the groundwork for the study of other novel therapies.